Dopamine receptor agonist stimulates neurogenesis & leads to functional recovery in Parkinsonian rats

A study published today in the Journal of Neuroscience shows that a drug which mimics the actions of dopamine can stimulate neurogenesis and lead to the recovery of motor functions in a rat model of Parkinson’s Disease (PD).

PD is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra (meaning ‘black substance’; the cells produce melanin and so are coloured black). The axons of these cells form the nigrostraital pathway, which is involved in the production of movement, and the death of these cells leads to the classical Parkinsonian symptoms of  tremors, stiffness and impaired balance and coordination.

One approach researchers have taken in trying to develop treatments for PD is to transplant embryonic stem (ES) cells or neural progenitors into the brain, in the hope that they will differentiate into dopaminergic neurons which can replace those that have degenerated. This approach has proved to be technically difficult, and many are ethically opposed to the use of ES cells.

Christopher Eckman and Jackalina Van Kampen, of the Mayo Clinic College of Medicine in Jacksonville, Florida, used a different approach. They injected the dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) into the ventricles of rats by 2-, 4- or 8-week continuous infusion.

Injections of bromodeoxyuridine (BrdU), which is incorporated into newly synthesized DNA, showed that 7-OH-DPAT stimulated endogenous stem cells in the rats’ brains to generate new dopaminergic neurons,  and injection of a fluorescent tracer showed that the cells extended their processes to the striatum.  

Approximately 28% of the newly-generated cells differentiated into dopaminergic midbrain neurons. Rats treated with 7-OH-DPAT for 8 weeks had 75% of the normal number of dopaminergic substantia nigra neurons, and recovered 80% of their motor functions; these effects were observed 4 months after treatment with the drug.

“This is the first study to show that endogenous neurogenesis can lead to recovery of function in an animal model of Parkinson’s disease,” says Dr. Eckman. “[7-OH-DPAT had] a profound behavioural effect…even after it ‘washed out’ of the system.”

7-OH-DPAT has never been used in humans, but two other drugs, pramipexole and ropinirole, have similar effects on dopamine receptors and have been approved for use in treating PD. Drs. Eckman and Van Kampen are now investigating the effects of these substances on neurogenesis, and are trying to determine if other drugs can stimulate genesis of the neurons that are lost in Alzheimer’s Disease and other neurodegenerative diseases.